tbuckley/cabot-search huggingface dataset:
Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases
Authors: Joni V. Lindbohm, Nina Mars, Pyry N. Sipilä, Archana Singh-Manoux, Heiko Runz, Gill Livingston, Sudha Seshadri, Ramnik Xavier, Aroon D. Hingorani, Samuli Ripatti, Mika Kivimäki
Journal: Nature Aging (2022)

Immune system and blood-brain barrier dysfunction are implicated in the development of Alzheimer's and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood-brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-β, tau and α-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n = 339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer's disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49-0.88, P = 0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases.
Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element
Authors: Jason A. Hall, Maria Pokrovskii, Lina Kroehling, Bo-Ram Kim, Seung Yong Kim, Lin Wu, June-Yong Lee, Dan R. Littman
Journal: Immunity (2022)

T helper 17 (Th17) cells regulate mucosal barrier defenses but also promote multiple autoinflammatory diseases. Although many molecular determinants of Th17 cell differentiation have been elucidated, the transcriptional programs that sustain Th17 cells in vivo remain obscure. The transcription factor RORγt is critical for Th17 cell differentiation; however, it is not clear whether the closely related RORα, which is co-expressed in Th17 cells, has a distinct role. Here, we demonstrated that although dispensable for Th17 cell differentiation, RORα was necessary for optimal Th17 responses in peripheral tissues. The absence of RORα in T cells led to reductions in both RORγt expression and effector function among Th17 cells. Cooperative binding of RORα and RORγt to a previously unidentified Rorc cis-regulatory element was essential for Th17 lineage maintenance in vivo. These data point to a non-redundant role of RORα in Th17 lineage maintenance via reinforcement of the RORγt transcriptional program.
Neurodevelopmental patterns of early postnatal white matter maturation represent distinct underlying microstructure and histology
Authors: Arash Nazeri, Željka Krsnik, Ivica Kostović, Sung Min Ha, Janja Kopić, Dimitrios Alexopoulos, Sydney Kaplan, Dominique Meyer, Joan L. Luby, Barbara B. Warner, Cynthia E. Rogers, Deanna M. Barch, Joshua S. Shimony, Robert C. McKinstry, Jeffrey J. Neil, Christopher D. Smyser, Aristeidis Sotiras
Journal: Neuron (2022)
Author Correction: Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance
Authors: Lige Leng, Ziqi Yuan, Ruiyuan Pan, Xiao Su, Han Wang, Jin Xue, Kai Zhuang, Ju Gao, Zhenlei Chen, Hui Lin, Wenting Xie, Huifang Li, Zhenyi Chen, Keke Ren, Xiao Zhang, Wenting Wang, Zi-Bing Jin, Shengxi Wu, Xinglong Wang, Zengqiang Yuan, Huaxi Xu, Hei-Man Chow, Jie Zhang
Journal: Nature Metabolism (2022)
Prognostic value of TARC and quantitative PET parameters in relapsed or refractory Hodgkin lymphoma patients treated with brentuximab vedotin and DHAP
Authors: Julia Driessen, Marie José Kersten, Lydia Visser, Anke van den Berg, Sanne H. Tonino, Josée M. Zijlstra, Pieternella J. Lugtenburg, Franck Morschhauser, Martin Hutchings, Sandy Amorim, Thomas Gastinne, Marcel Nijland, Gerben J. C. Zwezerijnen, Ronald Boellaard, Henrica C. W. de Vet, Anne I. J. Arens, Roelf Valkema, Roberto D. K. Liu, Esther E. E. Drees, Daphne de Jong, Wouter J. Plattel, Arjan Diepstra
Journal: Leukemia (2022)
Identification of bacterial lipopeptides as key players in IBS
Authors: Camille Petitfils, Sarah Maurel, Gaelle Payros, Amandine Hueber, Bahija Agaiz, Géraldine Gazzo, Rémi Marrocco, Frédéric Auvray, Geoffrey Langevin, Jean-Paul Motta, Pauline Floch, Marie Tremblay-Franco, Jean-Marie Galano, Alexandre Guy, Thierry Durand, Simon Lachambre, Anaëlle Durbec, Hind Hussein, Lisse Decraecker, Justine Bertrand-Michel, Abdelhadi Saoudi, Eric Oswald, Pierrick Poisbeau, Gilles Dietrich, Chloe Melchior, Guy Boeckxstaens, Matteo Serino, Pauline Le Faouder, Nicolas Cenac
Journal: Gut (2022)

Objectives Clinical studies revealed that early-life adverse events contribute to the development of IBS in adulthood. The aim of our study was to investigate the relationship between prenatal stress (PS), gut microbiota and visceral hypersensitivity with a focus on bacterial lipopeptides containing γ-aminobutyric acid (GABA). Design We developed a model of PS in mice and evaluated, in adult offspring, visceral hypersensitivity to colorectal distension (CRD), colon inflammation, barrier function and gut microbiota taxonomy. We quantified the production of lipopeptides containing GABA by mass spectrometry in a specific strain of bacteria decreased in PS, in PS mouse colons, and in faeces of patients with IBS and healthy volunteers (HVs). Finally, we assessed their effect on PS-induced visceral hypersensitivity. Results Prenatally stressed mice of both sexes presented visceral hypersensitivity, no overt colon inflammation or barrier dysfunction but a gut microbiota dysbiosis. The dysbiosis was distinguished by a decreased abundance of Ligilactobacillus murinus , in both sexes, inversely correlated with visceral hypersensitivity to CRD in mice. An isolate from this bacterial species produced several lipopeptides containing GABA including C14AsnGABA. Interestingly, intracolonic treatment with C14AsnGABA decreased the visceral sensitivity of PS mice to CRD. The concentration of C16LeuGABA, a lipopeptide which inhibited sensory neurons activation, was decreased in faeces of patients with IBS compared with HVs. Conclusion PS impacts the gut microbiota composition and metabolic function in adulthood. The reduced capacity of the gut microbiota to produce GABA lipopeptides could be one of the mechanisms linking PS and visceral hypersensitivity in adulthood.
Formula milk: WHO Foundation refuses to take further financial donations from Nestlé
Authors: Rebecca Coombes
Journal: BMJ (2022)

<h3>Background</h3> Complications and need for reinterventions are frequent in patients with pulmonary valve stenosis (PVS). Pulmonary regurgitation is common, but no data are available on outcome after pulmonary valve replacement (PVR). <h3>Methods</h3> We performed a retrospective analysis of 215 patients with PVS who underwent surgical valvotomy or balloon valvuloplasty. Incidence and predictors of reinterventions and complications were identified. Right ventricle (RV) remodelling after PVR was also assessed. <h3>Results</h3> After a median follow-up of 38.6 (30.9–49.4) years, 93% of the patients were asymptomatic. Thirty-nine patients (18%) had at least one PVR. Associated right ventricular outflow tract (RVOT) intervention and the presence of an associated defect were independent predictors of reintervention (OR: 4.1 (95% CI 1.5 to 10.8) and OR: 3.6 (95% CI 1.9 to 6.9), respectively). Cardiovascular death occurred in 2 patients, and 29 patients (14%) had supraventricular arrhythmia. Older age at the time of first intervention and the presence of an associated defect were independent predictors of complications (OR: 1.0 (95% CI 1.0 to 1.1) and OR: 2.1 (95% CI 1.1 to 4.2), respectively). In 16 patients, cardiac magnetic resonance before and after PVR was available. The optimal cut-off values for RV volume normalisation were 193 mL/m<sup>2</sup> for RV end-diastolic volume indexed(sensitivity 80%, specificity 64%) and 100 mL/m<sup>2</sup> for RV end-systolic volume indexed(sensitivity 80%, specificity 56%). <h3>Conclusions</h3> Previous RVOT intervention, presence of an associated defect and older age at the time of first repair were predictors of outcome. More data are needed to guide timing of PVR, and extrapolation of tetralogy of Fallot guidelines to this population is unlikely to be appropriate.
At last, a prestigious prize for global health
Authors: Ilona Kickbusch, Chikwe Ihekweazu
Journal: BMJ (2022)

<h3>Abstract</h3> <h3>Background</h3> The purpose of this analysis was to assess the variations in COVID-19 related mortality and incidence rates in relation to the time differences in the commencement of virus circulation and containment measures in different countries of the European Region. <h3>Methods</h3> The data for the current analysis (N=50 countries) were retrieved from the John Hopkins University dataset on the 7<sup>th</sup> of May 2020, with countries as study units. A piecewise regression analysis was conducted with mortality and cumulative incidence rates introduced as dependent variables and time interval (days from the 22<sup>nd</sup> of January to the date when 100 first cases were reported) as the main predictor. The country average life expectancy at birth was statistically adjusted for in the regression model. <h3>Results</h3> Mortality and incidence were strongly and inversely intercorrelated with days from January 22, respectively −0.83 (<i>p</i>&lt;.0001) and −0.73 (<i>p</i>&lt;.0001). Adjusting for average life expectancy, between days 33 to 50 from the 22th of the January, the average mortality rate decreased by 30.4/million per day (95% CI: 23.2, 37.1, <i>p</i>&lt;0.0001). During interval 51 to 73 days, the change in mortality was no longer statistically significant but still showed a decreasing trend. A similar relationship with time interval was found in incidence. Life expectancy was not associated with mortality rate. <h3>Conclusion</h3> Countries in Europe which observed the earliest COVID-19 circulation, suffered the worst consequences in terms of health outcomes, specifically mortality. The drastic social isolation measures, undertaken especially in Eastern European countries, where community circulation started after March 11<sup>th</sup>, may have been timely. This may explain their significantly lower COVID-related mortality compared with the Western European countries.
Population-based investigation of common and deviating patterns of gastric cancer and oesophageal cancer incidence across populations and time
Authors: Mengmeng Li, Jin Young Park, Mahdi Sheikh, Violet Kayamba, Harriet Rumgay, Mazda Jenab, Clement Tetteh Narh, Behnoush Abedi-Ardekani, Eileen Morgan, Catherine de Martel, Valerie McCormack, Melina Arnold
Journal: Gut (2022)

Background The subtypes of gastric cancer (GC) and oesophageal cancer (EC) manifest distinct epidemiological profiles. Here, we aim to examine correlations in their incidence rates and to compare their temporal changes globally, both overall and by subtype. Methods Long-term incidence data were obtained from population-based registries available from the Cancer Incidence in Five Continents series. Variation in the occurrence of EC and GC (overall and by subtype) was assessed using the GC:EC ratio of sex-specific age-standardised rates (ASR) in 2008–2012. Average annual per cent changes were estimated to assess temporal trends during 1998–2012. Results ASRs for GC and EC varied remarkably across and within world regions. In the countries evaluated, the GC:EC ratio in men exceeded 10 in several South American countries, Algeria and Republic of Korea, while EC dominated in most sub-Saharan African countries. High rates of both cardia gastric cancer and oesophageal squamous cell carcinoma (ESCC) were observed in several Asian populations. Non-cardia gastric cancer rates correlated positively with ESCC rates (r=0.60) and negatively with EAC (r=−0.79). For the time trends, while GC incidence has been uniformly decreasing by on average 2%–3% annually over 1998–2012 in most countries, trends for EC depend strongly on histology, with several but not all countries experiencing increases in EAC and decreases in ESCC. Conclusions Correlations between GC and EC incidence rates across populations are positive or inverse depending on the GC subsite and EC subtype. Multisite studies that include a combination of populations whose incidence rates follow and deviate from these patterns may be aetiologically informative.
Effect of endoscopic sleeve gastroplasty on gastric emptying, motility and hormones: a comparative prospective study
Authors: Eric J Vargas, Monika Rizk, Jacky Gomez-Villa, Phillip K Edwards, Veeravich Jaruvongvanich, Andrew C Storm, Andres Acosta, David Lake, Jeff Fidler, Adil E Bharucha, Michael Camilleri, Barham K Abu Dayyeh
Journal: Gut (2022)

Objective Endoscopic sleeve gastroplasty (ESG) has gained global adoption but our understanding of its mechanism(s) of action and durability of efficacy is limited. We sought to determine changes in gastric emptying (GE), gastric motility (GM), hormones and eating behaviours after ESG. Design A priori - designed single-centre substudy of a large US randomised clinical trial, adults with obesity were randomised to ESG or lifestyle interventions (LS) alone. We measured GE, hormones and weight loss and assessed eating behaviours. In a subset of ESG patients, we assessed GM. The primary outcome was the change in T 1/2 (min) at 3 months, and secondary outcomes were changes in weight, GE, GM, hormones and eating behaviours. We used t-test analyses and regression to determine the association between GE and weight loss. Results 36 (ESG=18; LS=18) participated in this substudy. Baseline characteristics were similar between the two groups. At 3 months, T 1/2 was delayed in the ESG group (n=17) compared with the LS group (n=17) (152.3±47.3 vs 89.1±27.9; p&lt;0.001). At 12 months, T 1/2 remained delayed in the ESG group (n=16) vs control group (n=14) (137±37.4 vs 90.1±23.4; p&lt;0.001). Greater delays in GE at 3 months were associated with greater weight loss. GM was preserved and fasting ghrelin, glucagon-like peptide 1 and polypeptide YY significantly increased 18 months after ESG. Conclusion ESG promotes weight loss through several key mechanistic pathways involving GE and hormones while preserving GM. These findings further support clinical adoption of this technique for the management of obesity. Trial registration number NCT03406975 .
Myeloablative autologous haematopoietic stem cell transplantation resets the B cell repertoire to a more naïve state in patients with systemic sclerosis
Authors: Julia Z Adamska, Amin Zia, Michelle S Bloom, Leslie J Crofford, Daniel E Furst, Ellen Goldmuntz, Lynette Keyes-Elstein, Maureen D Mayes, Peter McSweeney, Richard A Nash, Ashley Pinckney, Beverly Welch, Zelda Z Love, Keith M Sullivan, William Robinson
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Myeloablative autologous haematopoietic stem cell transplant (HSCT) was recently demonstrated to provide significant benefit over cyclophosphamide (CYC) in the treatment of diffuse cutaneous systemic sclerosis (dcSSc) in the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial. As dysregulation of the B cell compartment has previously been described in dcSSc, we sought to gain insight into the effects of myeloablative autologous HSCT as compared with CYC. Methods We sequenced the peripheral blood immunoglobulin heavy chain (IGH) repertoires in patients with dcSSc enrolled in the SCOT trial. Results Myeloablative autologous HSCT was associated with a sustained increase in IgM isotype antibodies bearing a low mutation rate. Clonal expression was reduced in IGH repertoires following myeloablative autologous HSCT. Additionally, we identified a underusage of immunoglobulin heavy chain V gene 5–51 in patients with dcSSc, and usage normalised following myeloablative autologous HSCT but not CYC treatment. Conclusions Together, these findings suggest that myeloablative autologous HSCT resets the IGH repertoire to a more naïve state characterised by IgM-expressing B cells, providing a possible mechanism for the elimination of pathogenic B cells that may contribute to the benefit of HSCT over CYC in the treatment of dcSSc.
Global epidemiology of systemic lupus erythematosus: a comprehensive systematic analysis and modelling study
Authors: Jingru Tian, Dingyao Zhang, Xu Yao, Yaqing Huang, Qianjin Lu
Journal: Annals of the Rheumatic Diseases (2022)

Objectives To quantify global, regional and country-specific estimates of epidemiology of systemic lupus erythematosus (SLE). Methods Four databases were systematically searched, and a Bayesian hierarchical linear mixed model was constructed to estimate the global, regional, and country-specific incidence and prevalence of SLE. Results 112 studies met the inclusion criteria. The global SLE incidence and newly diagnosed population were estimated to be 5.14 (1.4 to 15.13) per 100 000 person-years and 0.40 million people annually, respectively. In women, the values were 8.82 (2.4 to 25.99) per 100 000 person-years and 0.34 million people annually, while in men, the estimates were 1.53 (0.41 to 4.46) per 100 000 person-years and 0.06 million people annually, respectively. Poland, the USA and Barbados had the highest estimates of SLE incidence. Regarding prevalence, the global SLE prevalence and affected population were estimated to be 43.7 (15.87 to 108.92) per 100 000 persons and 3.41 million people, respectively. In women, the values were 78.73 (28.61 to 196.33) per 100 000 persons and 3.04 million people, while in men the estimates were 9.26 (3.36 to 22.97) per 100 000 persons and 0.36 million people, respectively. The United Arab Emirates, Barbados and Brazil had the highest SLE prevalence. In addition to regional and sex differences, age and prevalence estimation method (period or point prevalence) differences could also lead to variations in epidemiological SLE findings. Conclusions Epidemiological data on SLE are lacking for 79.8% of countries worldwide. The epidemiology of SLE varies substantially between different sex and age groups and is distributed unequally among geographical regions; specifically, SLE occurs more frequently in high-income countries.
RNA binding proteins (RBPs) and their role in DNA damage and radiation response in cancer
Authors: Meghna Mehta, Rajeswari Raguraman, Rajagopal Ramesh, Anupama Munshi
Journal: Advanced Drug Delivery Reviews (2022)

Traditionally majority of eukaryotic gene expression is influenced by transcriptional and post-transcriptional events. Alterations in the expression of proteins that act post-transcriptionally can affect cellular signaling and homeostasis. RNA binding proteins (RBPs) are a family of proteins that specifically bind to RNAs and are involved in post-transcriptional regulation of gene expression and important cellular processes such as cell differentiation and metabolism. Deregulation of RNA-RBP interactions and any changes in RBP expression or function can lead to various diseases including cancer. In cancer cells, RBPs play an important role in regulating the expression of tumor suppressors and oncoproteins involved in various cell-signaling pathways. Several RBPs such as HuR, AUF1, RBM38, LIN28, RBM24, tristetrapolin family and Musashi play critical roles in various types of cancers and their aberrant expression in cancer cells makes them an attractive therapeutic target for cancer treatment. In this review we provide an overview of i). RBPs involved in cancer progression and their mechanism of action ii). the role of RBPs, including HuR, in breast cancer progression and DNA damage response and iii). explore RBPs with emphasis on HuR as therapeutic target for breast cancer therapy.
Dampened Inflammation and Improved Survival After CXCL5 Administration in Murine Lupus via Myeloid and Neutrophil Pathways
Authors: Xiubo Fan, Chin Teck Ng, Dianyang Guo, Frances Lim, Jia Chi Tan, Annie Law, Lim Hee Goh, Zhi Yong Poon, Alice Cheung, Say Li Kong, Michelle Tan, Shang Li, Alwin Loh, Anne James, Tony Lim, Jinmiao Chen, Julian Thumboo, William Hwang, Andrea Low
Journal: Arthritis & Rheumatology (2022)

Objective To determine the efficacy of CXCL5 administration in lupus‐prone MRL/ lpr (Fas lpr ) mice and elucidate its working mechanisms. Methods CXCL5 expression in blood (obtained from SLE patients and Fas lpr mice) and major internal organs (obtained from Fas lpr mice) was examined by Luminex, real‐time polymerase chain reaction, and immunofluorescent staining analyses. Pharmacokinetic studies were performed in Fas lpr mice and healthy Institute of Cancer Research mice. Efficacy of CXCL5 administration was demonstrated in Fas lpr mice, and the working mechanism of CXCL5 treatment was elucidated by flow cytometry, Luminex, and RNA sequencing. Results In SLE patients, serum CXCL5 levels were significantly lower than in healthy individuals ( P &lt; 0.0001) and negatively correlated with disease activity ( P = 0.004). In Fas lpr mice, disease severity progressed with age and was negatively associated with plasma CXCL5 levels. Intravenous administration of CXCL5 to Fas lpr mice restored endogenous circulatory CXCL5, improved mice survival, and reduced anti–double‐stranded DNA antibodies, proteinuria, lupus nephritis activity and chronicity indices, renal complements, and neutrophil extracellular traps over short‐term (10 weeks) and long‐term (2 years) time periods. In vitro and in vivo assays demonstrated that CXCL5 dictated neutrophil trafficking and suppressed neutrophil activation, degranulation, proliferation, and renal infiltration. Renal and splenic RNA sequencing further showed that CXCL5‐mediated immunomodulation occurred by promoting energy production in renal‐infiltrated immune cells, activating certain T cells, and reducing tissue fibrosis, granulocyte extravasation, complement components, and interferons. Further factorial design results indicated that CXCL5 appears to enhance host tolerability to cyclophosphamide in vulnerable individuals. Conclusion We found that serum CXCL5 levels were significantly lower in SLE patients than in healthy individuals and were negatively correlated with disease activity. By administering CXCL5 intravenously in a mouse model of lupus, mouse survival improved, and indices of disease activity reduced significantly. Taken together, these findings indicate CXCL5 administration may represent a novel myeloid/neutrophil‐targeting therapy for SLE.